Psychedelic Research Recap February 2022
Psychedelic research shows no sign of slowing down as researchers carried over the New Year’s momentum into February. Over the last month, we saw that psilocybin-assisted therapy’s effects on depression could last for up to 12 months. MDMA-assisted therapy led to reductions in alcohol use in patients with PTSD. At the same time, the first study assessing the effects of MDMA on fear extinction retention took place in healthy adults. Researchers provided us with the foundation for designing safe and effective non-hallucinogenic psychedelic analogues.
You can find all the papers in our database and those that weren’t added in our February Link Overview.
The Trials That Took Them To The Test
February brought with it the results of many clinical trials involving human participants. Most notably, psilocybin was shown to alleviate symptoms of depression up to 12-months after dosing sessions. LSD was shown to influence the creative process whilst MDMA may have the potential for treating alcohol use disorder, which is often experienced comorbidly alongside PTSD.
The team at Johns Hopkins published the results from a 12-month follow-up (n=24) which assessed the efficacy and safety of psilocybin in depressed participants from a previous trial. A durable antidepressant effect was observed with treatment response (⩾50% reduction in GRID-HAMD score from baseline, Cohen d = 2.4) and rate of remission at 75% and 58%, respectively, at 12 months. No serious adverse events related to psilocybin were observed.
Lead author Dr Natalie Guksayan provided us with an insightful thread related to the results on Twitter. Despite the small sample size, these findings are significant for psilocybin-assisted therapy and psychedelic medicine.
This double-blind RCT (n=24) assessed the impact LSD (50μg) has on measures of creativity. Near peak drug effects, participants were given several creative tasks to complete. Creativity was then assessed by scoring creativity criteria, calculating divergent thinking and convergent thinking, computing semantic distances and searching for data-driven special features. Compared to placebo, LSD changed several creativity measurements pointing to pattern break, disorganization and meaning which seemed to fundamentally influence creative cognition and behaviour.
We had the chance to catch up with this study’s lead author, Isabelle Wießner, in our latest column with Lucid News.
Isabelle Wießner published another paper (n=24, same participants) that investigated the effects LSD (50 μg) has on a number of measures of cognition in healthy volunteers. It was found that LSD sub-acutely improved visuospatial memory, phonological verbal fluency and impaired cognitive flexibility when compared to placebo suggesting that LSD-assisted therapy may provide a novel treatment in conditions involving memory and language declines.
A similarly designed study with LSD (n=56) explored the effects of four repeated doses of LSD (13 or 26μg) on measures of mood and cognition. LSD administration sessions were separated by 3-4 days. LSD (26μg) produced modest subjective effects but it did not improve mood or affect performance. While LSD was safely administered, low doses of LSD produced negligible changes in mood or cognition in healthy volunteers.
This trial (n=90) assessed patterns of alcohol and substance use in patients receiving MDMA-assisted therapy. MDMA was associated with a significant reduction in Alcohol Use Disorder Identification Test (AUDIT) scores when compared to placebo. Changes in Drug Use Disorder Identification Test (DUDIT) scores did not significantly differ between groups.
In what is a first, a trial (n=34) assessed the effects of MDMA (100mg) following a fear acquisition session, an extinction training session and retention in healthy subjects. There was no difference between extinction training and retention between groups. However, significantly more participants in the MDMA group retained extinction learning compared to the placebo group (p = 0.007).
Researchers assessed clinical predictors of depressive symptom remission and response 24 h and 7 days after racemic ketamine and esketamine infusions in this double-blind RCT (n=61). Depressive symptoms were assessed using the MADRS. The number of treatment failures and the severity of illness were predictors of fewer remissions and responses to depressive symptoms.
A look inside the brain
The team at Imperial College London conducted a neuroimaging study (n=19) that used fMRI and ALFF techniques to assess the brain’s response to music following the administration of psilocybin to participants with treatment-resistant depression. The researchers identified music-related clusters in regions of the brain in which ALFF was significantly correlated with the intensity of subjective effects felt during the dosing sessions implying an elevated response to music following psilocybin therapy.
Researchers at Johns Hopkins used fMRI to compare the effects of a placebo (n=8) or a high dose of psilocybin (n=8). Greater functional connectivity in the default mode network (DMN) was observed in those who received psilocybin. Those who had received psilocybin reported significantly greater meaning, spiritual significance, psychological challenge, and psychological insight than those who had received the placebo.
Important Chemistry
Researchers have provided us with a foundation for the design of safe and effective non-hallucinogenic analogues. Here, they present structures of the serotonin receptor 5-HT2RA bound to psilocin, LSD, serotonin and the non-hallucinogenic analogue lisuride. The researchers were then able to design arrestin-biased ligands that displayed antidepressant-like activity in mice without hallucinogenic effects.
At the University of Basel, researchers explored the effects of several mescaline derivatives, scalines and 3C-scalines, on monoamine receptors in vitro. Scalines and 3C-scalines interacted with the 5-HT2A and 5-HT2C receptors, with preference to the 5-HT2A receptor, and bound with higher affinities (up to 63-fold and 34-fold increase, respectively) when compared to mescaline.
Reviews
The team at Drug Science explores the evidence to assess the psychological and psychiatric risks associated with psychedelics in this review. It was found that medical risks are often minimal and that nearly all of the negative perceptions of psychological risks associated with psychedelics are not supported by the current evidence.
These researchers explore the role and value of the setting in the psychedelic experience and the subsequent therapeutic outcomes. It was found that while the importance of setting is emphasized in the literature, there is yet to be any consistent and rigorous testing of setting and its complexities. There is yet to be a shared consensus on the effects setting has and the mechanism by which it affects outcomes as a result.
In this review, researchers discuss how psychedelics can be used to treat substance use disorders (SUDs) Specifically, the authors discuss the role of different forms of psychotherapy such as psychodynamic and cognitive behavioural.
What went on outside of the lab?
A survey study (n=411) assessed the factors that predict smoking cessation in people who reported quitting or reducing smoking following ayahuasca consumption. Mystical experience and frequency of ayahuasca intake were protective factors, while positive mood (measured by the MEQ30) during the ayahuasca experience was a risk factor. Qualitative analysis revealed eight themes related to the process of smoking cessation/reduction.
This large-scale survey (n=214,505) assessed the associations between lifetime use of classic psychedelics may share with cocaine use disorder (CUD) within a nationally representative sample of the U.S. Peyote (but not mescaline (the active ingredient in peyote), psilocybin, and LSD) use conferred lower odds of CUD.
Another survey (n=511) assessed the contextual factors associated with positive and negative mental health in recreational psychedelic users. Using psychedelics with high frequency and coping with negative affect were found to predict negative mental health. Conversely, using psychedelics in a group setting, with self-expansive intentions, and integrating post-use were found to predict positive mental health.
Researchers took a sociological perspective and discussed issues related to the medicalisation of psychedelic-assisted therapies. Three key areas discussed include the role of advocacy in the advancement of scientific research and the destigmatisation of psychedelics; issues related to medicalisation and pharmaceuticalisation; and integration into healthcare systems.
Papers Published in February 2022
34 studies from the Blossom database published this month.
Micro-dosing psychedelics as a plausible adjunct to psychosexual and couple’s therapy: a qualitative insight
This interview study (n=4 couples) explored the MDMA micro-dosing sexual experiences of four partnered men and women. Thematic analysis identified three key narratives: increased sexual self-efficacy; sexual exploration; and heightened relationship satisfaction. The use of microdosing MDMA had a positive effect on sexual and physical well-being by reducing stress and performance-related anxiety. Whilst higher doses of MDMA hindered sexual functioning this did not negatively impact the emotional and sensory experiences.
Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects
In a double‑blind crossover study in 28 healthy participants, high‑dose LSD (100–200 µg) and 30 mg psilocybin produced qualitatively and quantitatively similar acute subjective effects, with LSD showing longer duration and the 200 µg dose causing greater ego‑dissolution, cognitive impairment and anxiety. Cardiovascular responses differed (psilocybin raised blood pressure more, LSD increased heart rate more) but overall cardiostimulant load was comparable, indicating differences are dose‑dependent rather than substance‑specific and guiding dose selection for future research.
Updated cost-effectiveness of MDMA-assisted therapy for the treatment of posttraumatic stress disorder in the United States: Findings from a phase 3 trial
Using phase 3 trial data and a Markov model, MDMA-assisted therapy for severe or extreme chronic PTSD costs US$11,537 per patient and is cost-saving from a US payer perspective—producing discounted net health‑care savings of US$132.9 million per 1,000 patients, accruing 4,856 QALYs and averting 61.4 premature deaths over 30 years with a 3.8‑year payback. The more intensive three‑session phase 3 regimen yields greater medical savings and health benefits than shorter two‑session regimens.
Response to Intravenous Racemic Ketamine After Switch From Intranasal (S)-ketamine on Symptoms of Treatment-Resistant Depression and PTSD in Veterans: a Retrospective Case Series
In a retrospective case series of 15 veterans with treatment‑resistant depression and comorbid PTSD who switched from intranasal (S)‑ketamine to intravenous racemic (R,S)‑ketamine, IV treatment was associated with larger and statistically significant reductions in PHQ‑9 and PCL‑5 scores while reductions after IN (S)‑ketamine were smaller and not significant. The authors suggest IV racemic ketamine may be a reasonable next step for inadequate responders to IN (S)‑ketamine, but randomised, double‑blind trials are needed.
The Effects of Drugs on Behavior Maintained by Social Contact: Role of Monoamines in Social Reinforcement
This rodent study (2022) assessed the extent to which drugs that increase synaptic dopamine, norepinephrine, and serotonin enhance the positive reinforcing effects of social contact. Rats were given doses of a selective dopamine reuptake inhibitor, a selective norepinephrine reuptake inhibitor, a selective serotonin reuptake inhibitor, cocaine, d-amphetamine and MDMA. It was found that increases in extracellular dopamine, but not extracellular norepinephrine or serotonin, increase the positive reinforcing effects of social contact.
Ayahuasca and tobacco smoking cessation: results from an online survey in Brazil
This survey study (n=411) assessed the factors that predict smoking cessation in people who reported quitting or reducing smoking following ayahuasca consumption. Mystical experience and frequency of ayahuasca intake were protective factors, while positive mood (measured by the MEQ30) during the ayahuasca experience was a risk factor. Qualitative analysis revealed eight themes related to the process of smoking cessation/reduction.
Clinical predictors of depressive symptom remission and response after racemic ketamine and esketamine infusion in treatment-resistant depression
In a randomised, double‑blind trial of single subanaesthetic infusions of racemic ketamine or esketamine in 61 people with treatment‑resistant major depressive disorder, higher baseline illness severity and a greater number of prior treatment failures predicted poorer outcomes. Specifically, more treatment failures and greater severity were associated with lower odds of remission at 7 days and reduced likelihood of response at 24 hours.
MDMA and memory, addiction, and depression: dose-effect analysis
This rodent study (2022) assessed the effects of varying doses of MDMA (0.01 to 10mg/kg) on a number of fear conditioning variables. High doses of MDMA (≥ 3mg/kg) produced amnesia of fear conditioning memory, some evidence of addictive potential, and antidepressant effects, while low doses of MDMA (≤ 1mg/kg) had no effect on these behaviours. These findings suggest that the therapeutic use of MDMA below 3mg/kg is less likely to produce significant adverse cognitive effects.
Exploring protective associations between the use of classic psychedelics and cocaine use disorder: a population-based survey study
In a nationally representative US sample (NSDUH 2015–2019), lifetime peyote use was associated with a greater than 50% reduction in the odds of cocaine use disorder (adjusted OR 0.47) and lowered odds on seven of 11 CUD criteria, whereas psilocybin, LSD and mescaline showed no protective association or were linked to increased odds. The authors recommend studies to examine demographic, personality and contextual confounds and longitudinal research to determine causality and therapeutic potential.
A randomized controlled trial of 3,4-methylenedioxymethamphetamine (MDMA) and fear extinction retention in healthy adults
In a randomised, placebo-controlled trial of 100 mg MDMA in 34 healthy adults, MDMA was well tolerated but produced no overall group-level facilitation of fear extinction retention between extinction training and retention sessions. However, a significantly greater proportion of participants in the MDMA group retained extinction learning compared with placebo (χ2 = 7.29, p = 0.007), supporting further investigation of MDMA’s effects on extinction retention.
Asymmetry in Psychoactive Research: A Bibliometric Study on 15 Psychoactive Drugs
A bibliometric analysis of 956,703 publications on 15 psychoactive drugs (1960–2018) reveals asymmetric research attention: legal substances and depressants constituted 60–80% of the literature and different drugs showed heterogeneous growth patterns. The study also documents unexpected regional differences in output, implying cultural and political drivers and prompting governments and funders to rebalance research support to optimise therapeutic development and neuroscience knowledge.
Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up
In a randomised, waiting‑list controlled study of 27 adults with moderate–severe major depressive disorder who received two psilocybin doses with supportive psychotherapy, 24 completers showed large, durable reductions in GRID‑HAMD scores through 12 months (Cohen’s d ≈2.0–2.6), with 75% meeting response criteria and 58% achieving remission and no serious long‑term psilocybin‑related adverse events. Participant ratings of personal meaning, spiritual and mystical experience predicted increased well‑being at 12 months but did not predict antidepressant improvement.
Hallucinogenic drugs and their potential for treating fear-related disorders: Through the lens of fear extinction
This comprehensive review argues that hallucinogenic drugs can enhance fear extinction—by promoting neuroplasticity, tempering amygdala hyperreactivity and facilitating emotional engagement—and thus offer advantages over current first‑line treatments for fear‑related disorders. It highlights MDMA and ketamine as the most promising therapeutics to augment exposure therapy and examines the molecular mechanisms relevant to hallucinogen‑assisted psychotherapy.
Microdosing as a Response to the Meaning Crisis: A Qualitative Analysis
This qualitative analysis of 118 online reports identified four themes around reasons, practice, outcomes and meta-commentary of microdosing, and the authors argue—using meaning-making theory—that even sub-hallucinogenic doses can foster a sense of meaning by enhancing psychological flexibility and connectedness, with benefits reported regardless of initial motivation. The study highlights the need for double-blind, placebo-controlled trials to validate these self-reports.
Contextual Parameters Associated with Positive and Negative Mental Health in Recreational Psychedelic Users
This survey study (n=511) explored the contextual factors associated with positive and negative mental health in psychedelic users. Using psychedelics with high frequency and coping with negative affect were found to predict negative mental health. Conversely, using psychedelics in a group setting, with self-expansive intentions, and integrating post-use were found to predict positive mental health.
Ketamine as a Novel Psychopharmacotherapy for Eating Disorders: Evidence and Future Directions
This review (2022) explores the current evidence and future directions for using ketamine to treat eating disorders (EDs). Potential mechanisms of action, the role of psychotherapy and limitations are discussed.
The clinical pharmacology and potential therapeutic applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)
This review (2022) explores the current state of research surrounding 5-MeO-DMT. The authors provide food for thought on its therapeutic potential as well as the commercialization of the substance.
Trajectory of Antidepressant Effects after Single- or Two-Dose Administration of Psilocybin: A Systematic Review and Multivariate Meta-Analysis
This review & meta-analysis (s=10, n=226) finds that two (vs one) sessions and a higher dose of psilocybin (up to 30mg) were associated with better antidepressant effects. The meta-analysis showed a robust antidepressant effect up to 6 months later (d = -1.12).
Effects of Setting on Psychedelic Experiences, Therapies, and Outcomes: A Rapid Scoping Review of the Literature
This review (2022) explores the role and value of the setting in the psychedelic experience and the subsequent therapeutic outcomes. It was found that while the importance of setting is emphasized in the literature, there is yet to be any consistent and rigorous testing of setting and its complexities. There is yet to be a shared consensus on the effects setting has and the mechanism by which it affects outcomes as a result.
MDMA-Assisted Therapy for Posttraumatic Stress Disorder: A Mixed-Methods Case Study of a Participant of Color From an Open-Label Trial
In a mixed-methods case study of a participant of colour from an open-label MDMA-assisted therapy trial, MDMA-AT produced quantitative reductions in PTSD symptoms and interpretative phenomenological analysis identified psychological mechanisms of change alongside additional positive and negative effects. The study emphasises the importance of attending to culturally relevant material in MDMA-AT and offers recommendations for culturally attuned practice.
Receptor Interaction Profiles of 4-Alkoxy-3,5-Dimethoxy-Phenethylamines (Mescaline Derivatives) and Related Amphetamines
This study characterises the receptor profiles of 4-alkoxy-3,5-dimethoxy phenethylamines (scalines) and their amphetamine analogues (3C-scalines), finding they interact primarily with 5-HT2A and 5-HT2C receptors with weak-to-moderate affinity but up to 63‑fold and 34‑fold higher binding than mescaline. Extension or fluorination of the 4‑alkoxy substituent increased 5‑HT2A/2C affinity and 5‑HT2A activation potency, while non-serotonergic monoamine targets showed little potency.
The Effects of MDMA-Assisted Therapy on Alcohol and Substance Use in a Phase 3 Trial for Treatment of Severe PTSD
This trial (n=90) assessed patterns of alcohol and substance use in patients receiving MDMA-assisted therapy. MDMA was associated with a significant reduction in Alcohol Use Disorder Identification Test (AUDIT) scores when compared to placebo. Changes in Drug Use Disorder Identification Test (DUDIT) scores did not significantly differ between groups.
Neural Plasticity in the Ventral Tegmental Area, Aversive Motivation during Drug Withdrawal and Hallucinogenic Therapy
This review (2022) explores the ability of 5-HT2a receptor agonists (most classic psychedelics) to treat substance use disorders. The authors propose that the role of these receptors in BDNF dependent plasticity in the ventral tegmental area (VTA) of the dopamine system may offer a neurobiological explanation as to how 5-HT2a receptors exert their anti-addiction effects.
The frontiers of new psychedelic therapies: A survey of sociological themes and issues
This article surveys the sociological dimensions of the medicalisation of psychedelic‑assisted therapies, identifying advocacy, medicalisation/pharmaceuticalisation and health‑system integration as central issues and analysing regulation, stigma, monetisation and the socio‑political drivers of research and implementation. It contends these sociological dynamics will critically shape whether psychedelic medicine can be safely integrated as a potential paradigm shift in psychiatry.
Adverse effects of psychedelics: From anecdotes and misinformation to systematic science
This narrative review finds that medical harms from classic psychedelics are generally minimal and that many persistent fears about psychological risks are not supported by systematic evidence, with most adverse effects arising in unregulated settings. The authors emphasise the need for rigorous clinical standards and balanced media reporting to prevent stigma and allow responsible research to continue.
A retrospective analysis of the “Neverending Trip” after administration of a potent full agonist of 5-HT2A receptor - 25I-NBOMe
This retrospective analysis (2022) analysed 58 reports of adverse reactions caused by 25I-NBOMe (an uncommonly used psychedelic) to identify factors that may increase the risk of hallucinogen persisting perception disorder (HPPD) following its use. In 15 reports, symptoms persisted months after HPPD use the most common of which were: pseudohallucinations, bizarre delusions and derealization. Additionally, 25I-NBOMe induced HPPD can last from 2 months up to 2 years in some cases.
A Semantic Scale Network analysis of the revised Mystical Experiences Questionnaire: A call for collaboration
Semantic Scale Network analyses of the revised Mystical Experiences Questionnaire show the MEQ total and subscales have clear discriminant validity while conceptually overlapping with constructs such as awe, inspiration, regret, transcendence, depression, fatigue and spirituality. The paper proposes this item-based network approach as a collaborative tool to identify redundant measures, reveal novel links across literatures, and help researchers develop scales that add incremental validity in psychedelic research.
Adjunctive Ketamine With Relapse Prevention-Based Psychological Therapy in the Treatment of Alcohol Use Disorder
This double-blind placebo-controlled trial (n=96) assessed the effectiveness of 1) three weekly ketamine infusions (56mg/70kg i.v. over 40 minutes) plus psychological therapy, 2) three saline infusions plus psychological therapy, 3) three ketamine infusions plus alcohol education, or 4) three saline infusions plus alcohol education, in people with alcohol use disorder (AUD). Participants in the ketamine groups abstained from alcohol for a significantly longer number of days at 6-month follow-up, while the greatest abstinence was in the ketamine plus therapy group. Relapse times did not differ across the four groups.
Low-dose ketamine does not improve the speed of recovery from depression in electroconvulsive therapy: a randomized controlled trial
This randomised, double-blind, placebo-controlled study investigated the efficacy of using low-dose ketamine (35mg/70kg) as an anaesthetic adjunct to propofol during electroconvulsive therapy (ECT) for treating patients with depression (MDD). Adding ketamine did not alter the antidepressant efficacy or the hemodynamics of electroconvulsive therapy, although it may help reduce the dose requirements of propofol anaesthesia.
LSD and creativity: Increased novelty and symbolic thinking, decreased utility and convergent thinking
In a randomized, double‑blind, placebo‑controlled crossover with 24 healthy volunteers, 50 μg LSD increased novelty, surprise, originality and semantic distance while reducing utility and convergent thinking, producing a shift the authors characterise as pattern break, disorganisation and enhanced symbolic thinking. This reallocation of cognitive resources “away from normal” and “towards the new” suggests LSD‑induced symbolic thinking could be leveraged to improve outcomes in psychedelic‑assisted therapy.
Psychedelic treatment for co-occurring alcohol misuse and post-traumatic stress symptoms among United States Special Operations Forces Veterans
In a retrospective survey of 27 US Special Operations Forces veterans who completed a psychedelic treatment programme in Mexico, self‑reported alcohol misuse and post‑traumatic stress symptoms showed marked reductions with very large effect sizes (d≈–2.4 to –2.8) and 85% reduced drinking to non‑risky levels, while psychological flexibility increased. The uncontrolled, retrospective design limits causal inference, and the authors call for rigorous longitudinal trials to determine whether psychedelic‑assisted therapy is effective in this population.
Psychedelic use is associated with reduced daily opioid use among people who use illicit drugs in a Canadian setting
This longitudinal study (2021) assessed data from three ongoing open prospective cohorts of people who use drugs (PWUD) in Vancouver, Canada to investigate the relationship between psychedelic use and daily opioid use. This is the first study to find that recent psychedelic use was associated with 55% reduced odds of daily opioid use.
Repeated low doses of LSD in healthy adults: A placebo-controlled, dose-response study
In a double‑blind, placebo‑controlled study, healthy adults received four repeated low doses of LSD (13 or 26 μg) at 3–4‑day intervals. The 26 μg dose produced modest subjective drug effects but neither dose improved mood or cognitive/emotional task performance, no residual effects were detected at follow‑up, and the regimen was well tolerated in this controlled, limited‑administration setting.
The moderating role of mystical-type experiences on the relationship between existential isolation and meaning in life
This survey study (n=2055) explored if having a mystical-type experience impacted peoples levels of existential isolation (the subjective sense one is alone in one's experience) and subsequently, their levels of meaning in life. It was found that the previously reported negative impact levels of existential isolation have on a person's levels of meaning in life was not present in those who have had a mystical experience.